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11/6/2009
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Characteristics of Hematopoietic Stem Cells
Current Concepts in
All
Allogeneic
i Stem
St
Cell
C ll
Transplantation
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Sources of Stem Cells
• Frequency: 2-10 stem cells per 105 marrow cells
• Pluripotent: Give rise to all mature hematopoietic cell types
• Self-renewing: Can undergo cell division without differentiation
• Long-term reconstituting activity: Between 1 and 10
pluripotent stem cells can repopulate the entire hematopoiesis of a
mouse.
• Bone marrow
• Bloodstream
• Cord blood
• Quiescent or only slowly cycling
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11/6/2009
First marrow transplantation from an identical twin donor for refractory acute
lymphocytic leukemia by Dr. Thomas (Seattle), in 1958. Photo shows patient
4 weeks after transplant (right) and her donor.
History of Blood and Marrow Transplantation
1968
Good: First successful marrow transplant from an HLA-identical
sibling
1973
Speck: First marrow transplant from an unrelated donor
1977
Seattle Group: Results of HLA-identical sibling transplants in 100
patients with end-stage leukemia: 13 long-term disease-free survivors
1988
Gluckman: First successful cord blood transplant from an HLAidentical sibling
1990
Thomas: Awarded Nobel Prize in Medicine for endeavors in
experimental and clinical bone marrow transplantation
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Dr. E. Donall Thomas receives Nobel Prize
for Medicine from King Carl Gustav of
Sweden.
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Types of Stem Cell Transplants
Autologous:
The patient’s own stem cells are used.
Allogeneic:
Stem cells are obtained from an appropriate
related or unrelated donor.
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Stem Cell Transplantation Procedure
Collection of Peripheral Blood Stem Cells
by Leukapheresis
1) Harvest of stem cells from patient or appropriate
related or unrelated donor:
a) from pelvic bone in general anesthesia (marrow
stem cells)
b) from
f
arm veins
i by
b leukapheresis
l k h
i (peripheral
(
i h
l
blood stem cells)
c) from placenta after delivery (cord blood stem
cells)
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Stem Cell Transplantation Procedure
(continued)
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Intravenous Infusion of Blood Stem Cells
2) Treatment of patient with high dose chemotherapy
with or without high dose irradiation of whole body to:
a) destroy all tumor cells in the body of the patient
b) suppress the immune system of the patient to
prevent rejection of the allogeneic stem cell
transplant
3) Infuse stem cells into a central vein of the patient like
a blood transfusion.
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Indications and Numbers of
Allogeneic Hematopoietic Stem Cell Transplants
Worldwide in 2006
Strategy of Myeloablative Allogeneic
Stem Cell Transplant
1)
6,500
Conditioning with high doses of systemic chemotherapeutic
agents with or without additional TBI.
Unrelated donor (Total N=8,350)
Related donor (Total N=10,260)
6,000
2)
High dose therapy is designed to eradicate the underlying disease
and suppress the recipient’s immune system to prevent graft
rejection.
3)
Stem cell transplant to “rescue” the patient from the toxic effects
of the high-dose conditioning regimen on the bone marrow.
4)
Postgrafting immunosuppressive treatment is given to prevent
GVHD and to establish long-term graft / host tolerance.
5)
Toxicities of high-dose conditioning to GI tract, lung, heart and
liver have restricted the use of conventional, myeloablative
allogeneic SCT to younger, medically fit patients.
Number of Tran
nsplants
5,500
5,000
4,500
4,000
3,500
3,000
2,500
2,000
1,500
1,000
500
0
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AML
ALL
MDS/MPD
NHL
CML
Multiple
Myeloma
HD
Aplastic
Anemia
Other
Leuk
Other
Cancer
NonMalig
Disease
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One-Year Survival after a Myeloablative Conditioning Regimen
for Acute Leukemias in any Remission,
CML or MDS, Age 50 Years, 1988-2007,
by Year of Transplant and Graft Source
One-Year Surviva
al, percent
100
80
HLA-matched sibling
URD
Reduced Intensity Allogeneic
Reduced-Intensity
Stem Cell Transplantation
60
40
20
0
1988- 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
1990
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Institute
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SUM09_14.ppt
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11/6/2009
Age at Myeloablative SCT versus
Age at Diagnosis
Graft-versus-Tumor Effect after
Allogeneic Marrow Transplant
Median Age (years)
Allogeneic SCT Recipients (FHCRC)
Disease
Related Donor
At Diagnosis
Unrelated Donor
CML
40
36
67
AML
28
33
68
NHL
33
35
65
MM
45
45
70
CLL
51
46
71
HD
29
28
34
MDS
40
41
68
Overall
40 (n=1428)
35 (n=1277)
--
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Strategy of Reduced-Intensity
Stem Cell Transplant
Principle of Reduced-Intensity
Transplant
Tumor Cell Kill by Donor T-cells Instead of
Cytotoxic Chemo-Radiotherapy
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1) Non-myeloablative conditioning with purine analogues and
alkylating agents or low-dose TBI to suppress the immune
system of the recipient to allow engraftment.
2) Post-transplant
Post transplant immunosuppression with tacrolimus or
cyclosporine combined with mycophenolate mofetil and/or
anti-T-cell globulin to prevent GVHD and graft rejection.
3) Post-transplant immune manipulation by modifying immunosuppressive treatment or by infusion of donor lymphocytes
to increase donor chimerism and/or to improve disease
control.
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Effect of Post-transplant Immunosuppression on Engraftment of
DLA-Identical Marrow Grafts after Different Doses of TBI (Seattle)
Reduced-Intensity Hematopoietic Cell Transplant
Post-Transplant
# of Dogs w/Stable Engraftment/
TBI Dose (cGy)
Immunosuppression
# of Dogs Transplanted
920
None
20/21
450
None
16/39
450
7/7
450
CSP
Prednisone
200
CSP
0/4
200
MTX + CSP
2/5
200
100
MMF + CSP
MMF + CSP
11/12
0/6
100
MMF + CSP + CTLA4Ig*
4/6
0/5
* Peptide that binds to B7 and blocks T-cell-activating CD28: B7 pathway
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Candidates for Reduced-Intensity
Stem Cell Transplants
Non-Myeloablative Regimens
Center
Regimen
Donor
Postgrafting
Immunosuppression
Seattle
Flu + TBI (2 Gy)
MRD, URD
CSP + MMF
Houston
Flu + Mel
MRD, URD
FK-506 + MTX
Jerusalem
Flu + Bu + ATG
MRD, URD
CSP
London
Flu + Mel + Campath
MRD, URD
CSP + MTX
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Patients who are ineligible for myeloablative stem cell
transplants because of:
1) Age >55 years (related SCT) or > 50 years
(unrelated SCT)
2) Medical contraindications like renal, cardiac or
pulmonary insufficiencies.
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The Potential Benefits of Allotransplantation
Using a Non-Myeloablative Regimen
 Low toxicity and mortality
 Low anticipated late effects
 Treatment of elderly patients is feasible
 Suitable for treatment of patients with comorbid conditions
 Can be carried out on an out-patient basis
 Fast recovery with fewer complications and less infection
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Retrospective comparison of (a) transplant-related mortality and
(b) relapse in patients over 50 years of age with AML receiving
either a myeloablative (MA; n=407) or a reduced-intensity (RIC;
n=315) transplant from an HLA-identical sibling (EBMT)
TRM
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Retrospective comparison of (c) leukemia-free survival and (d) overall
survival in patients over 50 years of age with AML receiving either a
myeloablative (MA) or a reduced-intensity (RIC) transplant from an HLAidentical sibling (EBMT)
LFS
32%
44%
P < 0.001
18%
Relapse
41%
24%
NS
40%
OS
P < 0.0001
46%
44%
Aoudjhane M et al. Leukemia 2005; 19: 2304-2312
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NS
Aoudjhane M et al. Leukemia 2005, 19: 2304-2312
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11/6/2009
Probability of Survival After HLA-Identical Sibling
Transplants for AML, Age 50 Years, 1998–2006
Probability of Survival After HLA-Identical Sibling
Allotransplants for Follicular Lymphoma, 1998–2006
By Disease Status and Conditioning Regimen Intensity
By Disease Status and Conditioning Regimen
100
90
90
80
80
70
70
60
60
Early, myeloablative
Early, myeloablative
(N=660)(N=660)
50
50
40
40
30
30
Early, reduced-intensity conditioning (N=544)
Intermediate, myeloablative (N=206)
20
20
Intermediate, reduced-intensity conditioning (N=77)
10
10
P.3745.
0
3
Years
2
4
5
100
90
Chemosensitive, myeloablative (N=316)
70
60
60
50
50
Chemoresistant, reduced–intensity conditioning (N=46)
40
30
40
30
Chemoresistant, myeloablative (N=69)
20
20
10
10
P.0127.
0
0
0
1
2
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3
Years
4
5
6
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Autologous Transplantation Followed by
Reduced-Intensity Allogeneic Transplantation
in Myeloma
Probability of Survival After Transplants for Mantle
Cell Lymphoma, 1998–2006
By Donor Type and Conditioning Regimen
Probability of Su
urvival, %
80
70
6
100
90
Chemosensitive, reduced–intensity conditioning (N=325)
80
0
1
0
100
Probability of Su
urvival, %
Probability of Su
urvival, %
100
100
90
90
HLA-identical sibling, reduced-intensity conditioning (N=179)
80
80
HLA-identical sibling, myeloablative (N=258)
70
70
Autotransplant
p
((N=1,769))
,
))
60
60
50
Study
Maloney
50
40
Diagnosis
Relapsed, refractory or untreated
myeloma
Procedure
N
OS, %
DFS, %
Auto / Matched Sib
54
78
55
Double auto
Auto / Matched Sib
46
58
45
75
20
50
40
Bruno
Unrelated, myeloablative (N=63)
30
30
Unrelated, reduced-intensity conditioning (N=133)
20
Newly diagnosed myeloma
20
10
10
Antin JA. Hematology 2007; 47-54
P.0001.
0
0
0
1
2
3
Years
4
5
6
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11/6/2009
Conclusions
1. Reduced-intensity transplants are most successful in less
aggressive diseases such as low-grade lymphomas and
chronic lymphocytic leukemia because a graft-versus-tumor
reaction takes several weeks to develop after transplant.
2 M
2.
More aggressive
i diseases
di
like
lik AML,
AML MDS or aggressive
i
lymphomas have best results with RIC transplants if
diseases are in complete remission at the time of transplant.
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contents.
3. One strategy to obtain both dose intensity and a graftversus-malignancy effect is to follow a high-dose autologous
transplant with a RIC allogeneic transplant. This has been
shown, for instance, in multiple myeloma to improve both
event-free and overall survival.
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